Millions of people in the U.S. suffer from hearing loss caused by permanent damage to sensory hair cells of the inner ear. Hair cell damage often results from exposure to excessive sound in occupational or recreational settings such as industrial work or listening to loud music. There is a critical unmet need for greater understanding of the mechanisms underlying noise-induced hearing loss and for an experimental platform that can be used to quickly and objectively identify protective therapies. Without the development of novel therapeutics, noise-induced hearing loss will continue to have profound personal and economic consequences. The objective of this proposal is to develop the zebrafish lateral line as a valuable model for acoustic over-exposure using a precisely calibrated system of hair cell damage. Our central hypothesis is that the mechanism of noise-induced hair cell damage in the lateral line is similar to acoustic trauma in mammalian hair cells. The preliminary data presented in the approach demonstrate development of a continuous noise damage paradigm in the zebrafish lateral line capable of generating up to 50% hair cell death within three days of noise exposure. The rationale is that the zebrafish system will allow for future transformational research to understand cellular mechanisms of noise-induced hearing loss and to conduct thorough, quantitative, unbiased drug discovery research for novel hearing protectants. This project has two specific aims: 1) Determine the precise correlation between the duration and intensity of noise exposure and hair cell damage in the zebrafish lateral line, 2) Determine the relative contributions of caspase activation and oxidative stress to noise-induced hair cell death. These proposed studies will use a combination of targeted pharmacologic and live imaging coupled to optimization of a novel noise damage system customized for the zebrafish lateral line. This project is potentially innovative because we will develop the technical capability of precise regulation of the fluid dynamics delivering the noise that will induce damage. The contribution is expected to be the development of a unique in vivo experimental platform for noise-induced hearing loss research and further understanding cell death signaling in noise-damaged hair cells. These results would increase our fundamental understanding of mechanical hair cell damage and positively impact future drug discovery research.